EP2264025A1 - Procédé de production de forme cristalline de composés (II') - Google Patents
Procédé de production de forme cristalline de composés (II') Download PDFInfo
- Publication number
- EP2264025A1 EP2264025A1 EP10177460A EP10177460A EP2264025A1 EP 2264025 A1 EP2264025 A1 EP 2264025A1 EP 10177460 A EP10177460 A EP 10177460A EP 10177460 A EP10177460 A EP 10177460A EP 2264025 A1 EP2264025 A1 EP 2264025A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- substituent
- oxidation reaction
- solution
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000000034 method Methods 0.000 title claims abstract description 44
- 150000001875 compounds Chemical class 0.000 title description 60
- -1 imidazole compound Chemical class 0.000 claims abstract description 133
- 239000013078 crystal Substances 0.000 claims abstract description 67
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 47
- 125000001424 substituent group Chemical group 0.000 claims description 83
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 78
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 claims description 47
- 229960003174 lansoprazole Drugs 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 238000004519 manufacturing process Methods 0.000 claims description 29
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 26
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 239000012453 solvate Substances 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000002252 acyl group Chemical group 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 11
- 125000004423 acyloxy group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 229910021529 ammonia Inorganic materials 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 description 103
- 239000000243 solution Substances 0.000 description 60
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 22
- 125000004432 carbon atom Chemical group C* 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 230000033116 oxidation-reduction process Effects 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000007800 oxidant agent Substances 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- 238000002835 absorbance Methods 0.000 description 10
- 239000011259 mixed solution Substances 0.000 description 10
- 230000003647 oxidation Effects 0.000 description 10
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 9
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000013543 active substance Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 7
- 230000001590 oxidative effect Effects 0.000 description 7
- 150000003462 sulfoxides Chemical class 0.000 description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 6
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 6
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 5
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 5
- ZBFDAUIVDSSISP-UHFFFAOYSA-N 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine Chemical compound N=1C2=NC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C ZBFDAUIVDSSISP-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 238000009776 industrial production Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- FSJSYDFBTIVUFD-SUKNRPLKSA-N (z)-4-hydroxypent-3-en-2-one;oxovanadium Chemical compound [V]=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FSJSYDFBTIVUFD-SUKNRPLKSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 4
- 150000002460 imidazoles Chemical class 0.000 description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- 150000003682 vanadium compounds Chemical class 0.000 description 4
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- ADZARNIUZARQEL-UHFFFAOYSA-N 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfanyl]-1h-benzimidazole;hydrate Chemical compound O.CC1=C(OCC(F)(F)F)C=CN=C1CSC1=NC2=CC=CC=C2N1 ADZARNIUZARQEL-UHFFFAOYSA-N 0.000 description 3
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 3
- 0 CS(C1=NC(CCCCCCC2)C2N1*)=O Chemical compound CS(C1=NC(CCCCCCC2)C2N1*)=O 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- HRRXCXABAPSOCP-UHFFFAOYSA-N ilaprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC(=CC=C3N=2)N2C=CC=C2)=C1C HRRXCXABAPSOCP-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 3
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 3
- CMZUMMUJMWNLFH-UHFFFAOYSA-N sodium metavanadate Chemical compound [Na+].[O-][V](=O)=O CMZUMMUJMWNLFH-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 2
- PSIREIZGKQBEEO-UHFFFAOYSA-N 2-(1h-benzimidazol-2-ylsulfinylmethyl)-n-methyl-n-(2-methylpropyl)aniline Chemical compound CC(C)CN(C)C1=CC=CC=C1CS(=O)C1=NC2=CC=CC=C2N1 PSIREIZGKQBEEO-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical group C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000005079 alkoxycarbonylmethyl group Chemical group 0.000 description 2
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003699 antiulcer agent Substances 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 2
- 150000001555 benzenes Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- MJIHNNLFOKEZEW-RUZDIDTESA-N dexlansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1C[S@@](=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-RUZDIDTESA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229950008491 ilaprazole Drugs 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 229950007395 leminoprazole Drugs 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- SBQLYHNEIUGQKH-UHFFFAOYSA-N omeprazole Chemical compound N1=C2[CH]C(OC)=CC=C2N=C1S(=O)CC1=NC=C(C)C(OC)=C1C SBQLYHNEIUGQKH-UHFFFAOYSA-N 0.000 description 2
- 229960000381 omeprazole Drugs 0.000 description 2
- 229960005019 pantoprazole Drugs 0.000 description 2
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229950008375 tenatoprazole Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 1
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 description 1
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical group C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical group C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 1
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical group C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 description 1
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical group C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 1
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical group C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 description 1
- YHMYGUUIMTVXNW-UHFFFAOYSA-N 1,3-dihydrobenzimidazole-2-thione Chemical compound C1=CC=C2NC(S)=NC2=C1 YHMYGUUIMTVXNW-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000005978 1-naphthyloxy group Chemical group 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical group C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- MJIHNNLFOKEZEW-VWLOTQADSA-N 2-[(s)-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1h-benzimidazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1C[S@](=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-VWLOTQADSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000005979 2-naphthyloxy group Chemical group 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical group C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 1
- 125000005914 C6-C14 aryloxy group Chemical group 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229910019501 NaVO3 Inorganic materials 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical group C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Chemical group C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical class [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- GNILTGRCVCMPFJ-UHFFFAOYSA-N [3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methanol Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CO GNILTGRCVCMPFJ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000748 anthracen-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C([H])=C([*])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- UNTBPXHCXVWYOI-UHFFFAOYSA-O azanium;oxido(dioxo)vanadium Chemical compound [NH4+].[O-][V](=O)=O UNTBPXHCXVWYOI-UHFFFAOYSA-O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 210000000692 cap cell Anatomy 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical group C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005446 heptyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical group C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- MDDUHVRJJAFRAU-YZNNVMRBSA-N tert-butyl-[(1r,3s,5z)-3-[tert-butyl(dimethyl)silyl]oxy-5-(2-diphenylphosphorylethylidene)-4-methylidenecyclohexyl]oxy-dimethylsilane Chemical compound C1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C(=C)\C1=C/CP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 MDDUHVRJJAFRAU-YZNNVMRBSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000005287 vanadyl group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a method for producing an oxidized compound in a chemical/pharmaceutical field, with which a target oxidized compound is produced by an oxidation reaction, and more specifically relates to a method for producing an oxidized compound suitable for an industrial, large-scale production.
- the invention relates to a method for producing an oxidized compound, where the method is suitably used for producing a 2-(2-pyridyl- or phenyl-methylsulfinyl)imidazole compound (e.g., see U.S. Patent Publication No. 4,255,431 , European Unexamined Patent Publication No. 45,200 , European Unexamined Patent Publication No.
- the present inventors have conducted extensive studies to discover a production method advantageous in an industrial practice, with which 2-(2-pyridyl- or phenyl-methylsulfinyl) imidazoles can be produced from 2- (2-pyridyl- or phenyl-methylthio)imidazoles in good yield, less amount of byproducts such as corresponding sulfone products and 2-(2-pyridyl- or phenyl-methylsulfonyl)imidazole-N-oxides produced by overreaction are produced, and a computational management or the like is possible.
- the invention provides:
- Fig. 1 is a chart showing the change in the oxidation reduction potential of the oxidation reaction solution for an oxidation reaction which oxidizes a starting compound, SUL, with hydrogen peroxide using vanadyl acetylacetonate as a catalyst to obtain lansoprazole.
- Fig. 2 is a diagram schematically showing an exemplary apparatus for producing an oxidized compound of the invention.
- symbols in the diagram indicate as follows. 1: reactor, 2: oxidizing agent tank, 3: flow rate regulator, 4: oxidation reaction terminating agent tank, 5: ORP meter, 6: computer, 7: automatic valve, 8: monitor, 100: oxidized compound production system.
- the method of producing an oxidized compound of the invention is characterized in that an electric potential of an oxidation reaction solution for producing an oxidized compound is measured and then an end point of the oxidation reaction is determined on the basis of a predefined decrease of the electric potential, and preferably that when the electric potential of the oxidation reaction solution reaches to a highest electric potential, a point where the amount of an electric potential dropped from the highest electric potential reaches the predefined amount of an electric potential is determined as the end point of the oxidation reaction.
- An example of the oxidation reaction which can be applied for the invention include an oxidation reaction of obtaining a methylsulfinyl-substituted imidazole compound (hereinafter, referred to as compound (II')) having an aromatic heterocyclic ring such as pyridine or a benzene ring which may be substituted, from a methylthio-substituted imidazole compound represented by the following general formula (I') (hereinafter, referred to as compound (I')) having an aromatic heterocyclic ring such as pyridine or a benzene ring which may be substituted, with the use of an oxidizing agent.
- compound (II') methylsulfinyl-substituted imidazole compound having an aromatic heterocyclic ring such as pyridine or a benzene ring which may be substituted
- ring C' represents a benzene ring optionally having substituent (s) or a monocyclic aromatic heterocyclic ring optionally having substituent (s) ;
- R 0 represents a hydrogen atom, an aralkyl group optionally having substituent (s), an acyl group, or an acyloxy group;
- R 1 , R 2 , and R 3 are same as or different from each other and each of them represents a hydrogen atom, an alkyl group optionally having substituent(s), an alkoxy group optionally having substituent(s), or an amino group optionally having substituent(s);
- Y represents a nitrogen atom or CH].
- the ring C' represents "benzene ring optionally having substituent(s)” or "monocyclic aromatic heterocyclic ring optionally having substituent(s)".
- the "monocyclic aromatic heterocyclic ring” include 5- and 6-membered monocyclic aromatic heterocyclic rings such as furan, thiophen, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, and the like.
- the "benzene ring optionally having substituent(s)” and the “pyridine ring optionally having substituent(s)” are particularly preferable.
- the position for the "monocyclic aromatic heterocyclic ring" to condense with an imidazole moiety is not particularly limited.
- substituent for the ring C' examples include an alkyl group optionally having substituent(s), a halogen atom, a cyano group, a carboxy group, a carbamoyl group, a hydroxy group, an alkoxy group optionally having substituent(s), an acyl group, a carbamoyloxy group, a nitro group, an acyloxy group, an aryl group, an aryloxy group, an alkylthio group, a 5 to 10-membered heterocyclic group, and the like.
- alkyl group for the "alkyl group optionally having substituent(s)” groups having 1 to 7 carbon atoms are preferable, and examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, and the like.
- substituents for the "alkyl group optionally having substituent(s)” include a halogen atom, a hydroxy group, a C 1-6 alkoxy group (e.g., a methoxy group, an ethoxy group, a propoxy group, a butoxy group, etc.), a C 1-6 alkoxy-carbonyl group (e.g., a methoxy carbonyl group, an ethoxy carbonyl group, a propoxy carbonyl group, etc.), a carbamoyl group, and the like, and the number of the substituents may be from about 1 to 3. When the number of substituent is 2 or more, each substituent may be same as or different from each other.
- halogen atom examples include fluorine, chlorine, bromine, and the like, and among them, fluorine is preferable.
- alkoxycarbonylalkyl group groups in which each of the alkoxy and alkyl thereof has 1 to 4 carbon atoms are preferable, and examples thereof include a methoxycarbonylmethyl group (CH 3 OOCCH 2 -), a methoxycarbonylethyl group (CH 3 OOCC 2 H 4 -), an ethoxycarbonylmethyl group (C 2 H 5 OOCCH 2 -), an ethoxycarbonylethyl group (C 2 H 5 OOCC 2 H 4 -), and the like.
- alkoxy group for the "alkoxy group optionally having substituent (s) " groups having 1 to 6 carbon atoms are preferable, and examples include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a pentoxy group, and the like.
- substituents for the "alkoxy group optionally having substituent(s)" same ones as the "substituent” for the "alkyl group optionally having substituent (s) " can be exemplified, and the number of substituent is also the same.
- hydroxyalkyl group groups in which the alkyl thereof has 1 to 7 carbon atoms are preferable, and examples thereof include a hydroxymethyl group, an 1-hydroxy-propyl group, an 1-hydroxy-ethyl group, an 1-hydroxy-2-methyl-propyl group, and the like.
- acyl group examples include a formyl group, an alkylcarbonyl group, an alkoxycarbonyl group, a carbamoyl group, an alkylcarbamoyl group, an alkylsulfinyl group, an alkylsulfonyl group, and the like, and groups having 1 to 4 carbon atoms are preferable.
- alkylcarbonyl group examples include C 1-6 alkyl-carbonyl groups (e.g., an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, etc.), and the like.
- alkoxycarbonyl group examples include a C 1-6 alkoxy-carbonyl group (e.g., a methoxycarbonyl group (CH 3 OOC-), an ethoxycarbonyl group (C 2 H 5 OOC-), a propoxycarbonyl group, a butoxycarbonyl group, etc.), and the like, and groups in which the alkoxy thereof has 1 to 4 carbon atoms are preferable.
- a C 1-6 alkoxy-carbonyl group e.g., a methoxycarbonyl group (CH 3 OOC-), an ethoxycarbonyl group (C 2 H 5 OOC-), a propoxycarbonyl group, a butoxycarbonyl group, etc.
- alkylcarbamoyl group examples include N-C 1-6 alkyl-carbamoyl groups (e.g., a methylcarbamoyl group (CH 3 NHCO-), an ethylcarbamoyl group (C 2 H 5 NHCO-), etc.), an N,N-diC 1-6 alkyl-carbamoyl group (e.g., an N,N-dimethylcarbamoyl group, an N,N-diethylcarbamoyl group, etc.), and the like, and groups in which the alkyl thereof has 1 to 4 carbon atoms are preferable.
- N-C 1-6 alkyl-carbamoyl groups e.g., a methylcarbamoyl group (CH 3 NHCO-), an ethylcarbamoyl group (C 2 H 5 NHCO-), etc.
- alkylsulfinyl group examples include C 1-7 alkylsulfinyl groups (e.g., a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, an isopropylsulfinyl group, etc.), and the like, and groups having 1 to 6 carbon atoms are preferable.
- alkylsulfonyl group examples include C 1-7 alkylsulfonyl groups (e.g., a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, etc.), and the like.
- acyloxy group examples include a formyloxy group, an alkylcarbonyloxy group, an alkoxycarbonyloxy group, a carbamoyloxy group, an alkylcarbamoyloxy group, an alkylsulfinyloxy group, an alkylsulfonyloxy group, and the like.
- alkylcarbonyloxy group examples include C 1-6 alkyl-carbonyloxy groups (e.g., an acetyloxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, etc.) and the like, and groups in which the alkyl thereof has 1 to 4 carbon atoms are preferable.
- alkoxycarbonyloxy group examples include C 1-6 alkoxy-carbonyloxy groups (e.g., a methoxycarbonyloxy group, an ethoxycarbonyloxy group, a propoxycarbonyloxy group, a butoxycarbonyloxy group, etc.), and the like.
- alkylcarbamoyloxy group examples include C 1-6 alkyl-carbamoyloxy groups (e.g., a methylcarbamoyloxy group, an ethylcarbamoyloxy group, etc.), and the like.
- alkylsulfinyloxy group examples include C 1-7 alkylsulfinyloxy groups (e.g., a methylsulfinyloxy group, an ethylsulfinyloxy group, a propylsulfinyloxy group, an isopropylsulfinyloxy group, etc.), and the like.
- alkylsulfonyloxy group examples include C 1-7 alkylsulfonyloxy groups (e.g., a methylsulfonyloxy group, an ethylsulfonyloxy group, a propylsulfonyloxy group, an isopropylsulfonyloxy group, etc.), and the like.
- aryl group examples include C 6-14 aryl groups (e.g., a phenyl group, a tolyl group, an 1-naphthyl group, a 2-naphthyl group, a biphenyl group, a 2-anthryl group, etc.), and the like.
- aryloxy group examples include C 6-14 aryloxy groups (e.g., a phenyloxy group, a tolyloxy group, an 1-naphthyloxy group, a 2-naphthyloxy group, etc.), and the like.
- alkylthio group groups in which the alkyl thereof has 1 to 6 carbon atoms are preferable, and examples thereof include a methythio group, an ethylthio group, a propylthio group, and the like.
- Examples of the "5- to 10-membered heterocyclic group” include 5- to 10-membered (preferably 5 or 6 membered) heterocyclic groups having one or more (e.g., 1 to 3) hetero atom(s) selected from a nitrogen atom, a sulfur atom, and an oxygen atom, other than the carbon atom, and specific examples include a 2- or 3-thienyl group, a 2-, 3-, or 4-pyridyl group, a 2- or 3-furyl group, an 1-, 2-, or 3-pyrrolyl group, a 2-, 3-, 4-, 5-, or 8-quinolyl group, an 1-, 3-, 4-, or 5-isoquinolyl group, an 1-, 2-, or 3-indolyl group, and the like.
- 5- or 6-membered heterocyclic groups such as an 1-, 2-, or 3-pyrrolyl group are preferable.
- the substituent of the ring C' may be substituted by 1 to about 3 to a benzene ring, or may be substituted by 1 to 4 to a substitutable position of a monocyclic aromatic heterocyclic ring. When the number of substituent is 2 or more, each substituent may be same as or different from each other.
- a halogen atom, an alkyl group optionally having substituent(s), an alkoxy group optionally having substituent(s), and the like are preferable. It is particularly preferable that the ring C' is not substituted or substituted on the 4- or 5-position with an alkyl group, a halogen atom, a trifuloromethyl group, an alkoxy group or the like among the above substituents.
- the "aralkyl group” for the “aralkyl group optionally having substituent(s)” represented by R 0 can be exemplified by a C 7-16 aralkyl group (e.g., C 6-10 aryl C 1-6 alkyl groups such as a benzyl group and a phenethyl group), or the like.
- a C 7-16 aralkyl group e.g., C 6-10 aryl C 1-6 alkyl groups such as a benzyl group and a phenethyl group
- substituents for the "aralkyl group optionally having substituent(s)
- the number of substituent is from about 1 to 4. When the number of substituent is 2 or more, each substituent may be same as or different from each other.
- the "acyl group” represented by R 0 can be exemplified by the "acyl group” mentioned above as the substituent of the ring C'.
- acyloxy group represented by R 0 can be exemplified by the "acyloxy group” mentioned above as the substituent of the ring C'.
- the R 0 is preferably a hydrogen atom.
- the R 0 may be an N-protecting group.
- the N-protecting group include an alkyl group, an acyl group, an alkoxycarbonyl group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, an alkylcarbonylmethyl group, an alkoxycarbonylmethyl group, an alkylsulfonyl group, and the like.
- the alkyl group preferably has 1 to 5 carbon atoms, and examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, and the like.
- alkylcarbamoyl group is represented by the following formula: , in which the alkyl preferably has 1 to 4 carbon atoms, and examples include a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, an isopropylcarbamoyl group, and the like.
- the dialkylcarbamoyl group is represented by the following formula: , in which the alkyls preferably have each 1 to 4 carbon atoms, and examples include a dimethylcarbamoyl group, a diethylcarbamoyl group, anN-methyl-N-ethylcarbamoyl group, and the like.
- the alkylcarbonylmethyl group is represented by the formula: alkyl-CO-CH 2 -, in which the alkyl preferably has 1 to 4 carbon atoms, and examples include an acetylmethyl group, a propionylmethyl group, and the like.
- the alkoxycarbonylmethyl group is represented by the formula: alkyl -OCO-CH 2 -, in which the alkyl preferably has 1 to 4 carbon atoms, and examples include a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, and the like.
- the alkylsulfonyl group is represented by the formula: alkyl-SO 2 -, in which the alkyl preferably has 1 to 4 carbon atoms, and examples include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, and the like.
- the "alkyl group optionally having substituent (s)" represented by R 1 , R 2 or R 3 can be exemplified by the same group as the "alkyl group optionally having substituent(s)" mentioned above for the substituent of the ring C'.
- a fluorine-substituted alkyl group (preferably having 1 to 4 carbon atoms), e.g., a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a 2,2,3,3,3-pentafluoropropyl group, a 1-(trifluoromethyl)-2,2,2-trifluoroethyl group, a 2,2,3,3-tetrafluoropropyl group, a 2,2,3,3,4,4,4-heptafluorobutyl group, etc, can be exemplified.
- alkoxy group optionally having substituent(s) represented by R 1 , R 2 , or R 3
- same group as the "alkoxy group optionally having substituent(s)" mentioned above for the substituent of the ring C' can be exemplified, but it is preferable that the alkoxy group has 1 to 8 carbon atoms (e.g., a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a pentoxy group, a hexyloxy group, a heptyloxy group, an octyloxy group, etc.).
- a fluorine-substituted alkoxy group e.g., a 2,2,2-trifluoroethoxy group, a 2,2,3,3,3-pentafluoropropoxy group, a 1-(trifluoromethyl)-2,2,2-trifluoroethoxy group, a 2,2,3,3-tetrafluoropropoxy group, a 2,2,3,3,4,4,4-heptafluorobutoxy group, a 2,2,3,3,4,4,5,5-octafluoropentoxy group, etc, can be exemplified.
- a fluorine-substituted alkoxy group e.g., a 2,2,2-trifluoroethoxy group, a 2,2,3,3,3-pentafluoropropoxy group, a 1-(trifluoromethyl)-2,2,2-trifluoroethoxy group, a 2,2,3,3-tetrafluoropropoxy group, a 2,2,3,3,4,4,4-heptaflu
- Examples of the "amino group optionally having substituent (s)" represented by R 1 , R 2 , or R 3 include an amino group, a mono-C 1-6 alkylamino group (e.g., a methylamino group, an ethylamino group, etc.), a mono -C 6-14 arylamino group (e.g., a phenylamino group, an 1-naphthylamino group, a 2-naphthylamino group, etc.), a di-C 1-6 alkylamino group (e.g., a dimethylamino group, a diethylamino group, etc.), a di-C 6-14 arylamino group (e.g., a diphenylamino group), and the like.
- a mono-C 1-6 alkylamino group e.g., a methylamino group, an ethylamino group, etc.
- the R 1 is preferably a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkoxy group, or a di-C 1-6 alkylamino group.
- the R 1 is more preferably a C 1-3 alkyl group or a C 1-3 alkoxy group.
- the R 2 is preferably a hydrogen atom, a C 1-6 alkoxy -C 1-6 alkoxy group, or a C 1-6 alkoxy group which may be halogenated.
- the R 2 is more preferably a C 1-3 alkoxy group which is halogenated or may be substituted with a C 1-3 alkoxy group.
- the R 3 is preferably a hydrogen atom or a C 1-6 alkyl group.
- the R 3 is more preferably a hydrogen atom or a C 1-3 alkyl group, but particularly preferably is a hydrogen atom.
- Y represents a nitrogen atom or CH, and preferably Y is a nitrogen atom.
- ring A represents a benzene ring optionally having substituent(s), R 0 , R 1 , R 2 , R 3 , and Y have the same meaning as in the above-mentioned formulae (I') and (II').
- the preferred compound has a ring A which is a benzene ring optionally having 1 or 2 substituent(s) selected from a halogen atom, a C 1-4 alkyl group which may be halogenated, a C 1-4 alkoxy group which may be halogenated, and 5- or 6-membered heterocyclic group;
- R 0 which is a hydrogen atom, an aralkyl group which may be substituted, an acyl group, or an acyloxy group;
- R 1 which is a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkoxy group, or a di-C 1-6 alkylamino group;
- R 2 which is a hydrogen atom, a C 1-6 alkoxy-C 1-6 alkoxy group, or a C 1-6 alkoxy group which may be halogenated;
- R 3 which is a hydrogen atom or a C 1-6 alkyl
- the ring A is either non-substituted or substituted on the 4- or 5-position with a methoxy group or a trifluoromethyl group
- R 0 is a hydrogen atom
- R 1 and R 3 are same as or different from each other and each a hydrogen atom or a methyl group
- R 2 is a fluorinated alkoxy group having 2 to 5 carbon atoms.
- the target oxidized compound (II) is particularly preferably the compound represented by the formula (IIa): [wherein, R 1 represents a C 1-3 alkyl group or a C 1-3 alkoxy group; R 2 represents a C 1-3 alkoxy group which is halogenated or may be substituted with a C 1-3 alkoxy group; R 3 represents a hydrogen atom or a C 1-3 alkyl group; R 4 represents a hydrogen atom, a C 1-3 alkoxy group which may be halogenated, or a pyrrolyl group (e.g., 1-, 2- or 3-pyrrolyl group)].
- R 1 represents a C 1-3 alkyl group or a C 1-3 alkoxy group
- R 2 represents a C 1-3 alkoxy group which is halogenated or may be substituted with a C 1-3 alkoxy group
- R 3 represents a hydrogen atom or a C 1-3 alkyl group
- R 4 represents a hydrogen atom, a C 1-3
- the compound has R 1 which is a C 1-3 alkyl group, R 2 which is a C 1-3 alkoxy group which may be halogenated, R 3 which is a hydrogen atom, and R 4 which is a hydrogen atom or a C 1-3 alkoxy group which may be halogenated.
- an imidazopyridine compound of which the ring C' is a pyridine ring is also preferable.
- Such compound can be exemplified by 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfi nyl]-1H-imidazo[4,5-b]pyridine (tenatoprazole (TU-199)).
- optically active substances of lansoprazole that is, optically active substances such as (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl ]sulfinyl]-1H-benzimidazole (R-form of lansoprazole) and (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl ]sulfinyl]-1H-benzimidazole (S-form of lansoprazole) are particularly preferable for the invention.
- lansoprazole, lansoprazole R-form, and lansoprazole S-form are in crystal,
- salts of the compounds (I'), (II'), (I), (II), and (IIa) pharmaceutically acceptable salts are preferable, and examples include salts with an inorganic base, salts with an organic base, salts with a basic amino acid, and the like.
- the salts with an inorganic base include alkali metal salts such as a sodium salt and a potassium salt; alkaline earth metal salts such as a calcium salt and a magnesium salt; ammonium salts, and the like.
- Examples of the salts with an organic base preferably include salts with alkylamine (trimethylamine, triethylamine, etc.), heterocyclic amine (pyridine, picoline, etc.), alkanolamine (ethanolamine, diethanolamine, triethanolamine, etc.), dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like.
- alkylamine trimethylamine, triethylamine, etc.
- heterocyclic amine pyridine, picoline, etc.
- alkanolamine ethanolamine, diethanolamine, triethanolamine, etc.
- dicyclohexylamine N,N'-dibenzylethylenediamine, and the like.
- salts with an organic base preferably include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine[tris(hydroxymethyl)methylamine], t-butylamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like.
- Examples of the salts with a basic amino acid preferably include salts with arginine, lysine, ornithine, and the like.
- the alkali metal salts and the alkaline earth metal salts are preferable.
- the sodium salt is preferable.
- the compound (II') is preferably lansoprazole, omeprazole, rabeprazole, pantoprazole, leminoprazole, ilaprazole, tenatoprazole (TU-199), or the like, or optically active substance thereof or pharmaceutically acceptable salt thereof, and is more preferably lansoprazole or the optically active substance thereof, particularly the R-form.
- the oxidizing agent useful for the invention is not limited, and commonly used oxidizing agent can be employed.
- the oxidation can be carried out according to the method disclosed in Japanese Unexamined Patent Publication No. S61-50978 , Japanese Unexamined Patent Publication No. H01-131176 , U.S Patent Publication No. 4,628,098 , Japanese Unexamined Patent Publication No. H10-195068 , Pamphlet of International Publication WO 98/21201 , Japanese Unexamined Patent Publication No. S52-62275 , or Japanese Unexamined Patent Publication No. 54-141783 , or a method analogous thereto.
- oxidation carried out using hydrogen peroxide as an oxidizing agent is particularly preferable among others.
- a vanadium compound is particularly preferable among others.
- vanadium pentoxide V 2 O 5
- sodium metavanadate NaVO 3
- ammonium metavanadate NH 4 VO 3
- vanadyl acetylacetonate (CH 3 COCH 2 COCH 3 ) 2 VO]
- vanadium pentoxide, sodium metavanadate, and vanadyl acetylacetonate are used.
- the used amount of the vanadium compound is in the range of usually about 0.01 to 10 mol%, preferably about 0.05 to 2 mol%, and particularly preferably about 0.1 to 0.5 mol%, to the compound (I').
- hydrogen peroxide an aqueous hydrogen peroxide solution is usually used, but a solution state of an organic solvent such as n-butyl alcohol may also be used.
- concentration of hydrogen peroxide to be used is in the range of usually 10 to 70% and preferably 20 to 40%, but is not particularly limited by these ranges.
- Hydrogen peroxide may be usually used in a slightly excessive amount, preferably from about 1 to 3 equivalent amount, and more preferably from about 1 to 1.5 equivalent amount, to 1 equivalent amount of the compound (I').
- the solvent to be used in the reaction halogenated hydrocarbons such as chloroform and dichloromethane, ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide, alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methylethylketone, nitriles such as acetonitrile, water, or the like can be mentioned, and methanol, ethanol, acetone, and acetonitrile are preferably used and ethanol is particularly preferably used. These solvents may be used alone or in combination.
- the amount of a solvent to be used in the reaction is from about 0.5 to 10 L and preferably from about 1 to 5 L, per 1 mol of the compound (I'), but
- the reaction temperature is under ice-cooling to near the boiling point of the solvent to be used, usually is from under ice-cooling to about 40°C, and more preferably from about 15 to 30°C.
- the reaction time is usually from about 0.5 to 24 hours, and more preferably from about 1 to 8 hours.
- the target compound (II') produced by the above oxidation reaction usually precipitates as a crystal from the reaction solution, thus excessive hydrogen peroxide after the reaction can be decomposed by adding an oxidation reaction terminating agent (e.g., an aqueous sodium thiosulfate solution, etc.), and the precipitated crystals can be filtered to be isolated, but if necessary, the solvent extraction with chloroform or the like may be carried out, followed by concentration to be isolated.
- the isolated crystals can be purified by conventional means such as recrystallization, chromatography, and the like, if necessary.
- the optically active substance of the compound (II') can be obtained by optically resolving a racemate of the compound (II') produced by the above oxidation reaction, with the use of the optical resolution method (fractional recrystallization method, a chiral column method, a diastereomer method, a method using a microorganism or enzyme, etc.), or can be directly obtained by carrying out an asymmetrical oxidation for the above-mentioned oxidation reaction.
- the optical resolution method fractional recrystallization method, a chiral column method, a diastereomer method, a method using a microorganism or enzyme, etc.
- R-form of lansoprazole can be produced with the above oxidation reaction, for example, in accordance with the production method disclosed in Pamphlet of International Publication WO 00/78745 , Pamphlet of International Publication WO 01/83743 , and the like.
- the starting compound (I') can be produced, for example, in accordance with the method disclosed in U.S Patent Publication No. 4,255,431 , European Patent Publication No. 45,200 , European Patent Publication No. 74,341 , European Patent Publication No. 80,602 , European Patent Publication No. 5,129 , European Patent Publication No. 174,726 , European Patent Publication No. 175,464 , United Kingdom Patent Publication No. 2,134,523A , and the like.
- an electric potential of an oxidation reaction solution for producing an oxidized compound is measured, and an end point of the oxidation reaction is determined on the basis of a predefined decrease of the electric potential. Therefore, it is preferable to use an oxidation reduction potential (ORP) meter for an electric potential measurement of the oxidation reaction solution.
- ORP oxidation reduction potential
- a reactor for carrying out the oxidation reaction is not particularly limited, and can be appropriately selected from various reactors according to the target oxidized compound (oxidation reaction).
- the oxidation reaction in the invention is not particularly limited, and can be exemplified by oxidation reaction of sulfide to sulfoxide, oxidation reaction of alcohol to ketone, oxidation reaction of aldehyde to carboxylic acid, oxidation reaction of amine to nitroso, oxidation reaction of phosphine to phosphine oxide, or the like, and preferably exemplified by the oxidation reaction of sulfide (e.g., the imidazole compound represented by the above-mentioned formula (I) or (I') or salts thereof) to sulfoxide (e.g., an oxidized compound of the imidazole compound represented by the above-mentioned formula (II) or (II') or salts thereof).
- sulfide e.g., the imidazole compound represented by the above-mentioned formula (I) or (I') or salts thereof
- sulfoxide
- a system in which a sensor (submersion type, etc.) for the oxidation reduction potential (ORP) meter is attached to the reactor for carrying out the oxidation reaction, the oxidation reduction potential of the oxidation reaction solution in the reactor is monitored at all time, a highest point for the electric potential to reach is determined by a program, and then a point where the electric potential is rapidly decreased is determined as the end point of the oxidation reaction.
- the program is preferably incorporated in the operation of informing the operator that the reaction is finished and stopping the reaction.
- the termination of the oxidation reaction can be carried out, for example, by removing a starting material such as an oxidizing agent provided in excess, or the like.
- a starting material such as an oxidizing agent provided in excess, or the like.
- the oxidation reaction is preferably terminated by introducing an aqueous sodium thiosulfate solution (oxidation reaction terminating agent) to the oxidation reaction solution to decompose the unreacted hydrogen peroxide.
- oxidation reaction terminating agent examples include sodium sulfite, sodium hydrogensulfite, and the like, in addition to the aforementioned aqueous sodium thiosulfate solution.
- lansoprazole by using 2-(((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methyl)thi o)benzimidazole monohydrate (hereinafter, also may be referred to as SUL) as a starting compound (I'), ethanol as a reaction solvent, and vanadyl aceylacetonate as a catalyst, and oxidizing with hydrogen peroxide, when the oxidizing agent (hydrogen peroxide) is added dropwise over 10 to 30 minutes, then reacted at 20 to 21°C, and the oxidation reduction potential of the reaction solution is monitored with an ORP meter, the electric potential follows the time course shown in Fig. 1 . That is, the electric potential gradually increases, and when drops by about 70 mV after reaching to the highest electric potential, this dropped point can be determined as the reaction end point.
- SUL 2-((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methyl)thi
- the end point corresponds to a point where the spot size of the starting material SUL comes within the range of about 1 to 3% of the SUL standard solution when the reaction solution is observed with TLC, the starting compound SUL is almost consumed, and that the oxidation is completed.
- any ORP meter model can be employed, but in an industrial production, a meter in which an ORP transmitter can be equipped with an ORP sensor is preferable in order to enable a computational control.
- a sensor defect, etc. can be monitored during the ORP measurement, thus is suitable for a large-scale apparatus in a factory.
- ORP meter for example, OR8EFG-PT-05-TT2-NN * A manufactured by Yokogawa Electric Corp. can be mentioned.
- Fig. 2 shows a specific example of an oxidized compound production system carrying out the method of the invention in an industrial scale.
- the system 100 is constructed in the manner to dropwisely introduce an oxidizing agent stored in the oxidizing agent tank 2 by the flow rate regulator 3 into the reactor 1 which accommodates a starting compound (solution), and to supply an oxidation reaction terminating agent stored in the oxidation reaction terminating agent tank 4 in a predetermined amount to the reactor 1.
- the temperature condition of the reactor 1 and the like are set to predetermined conditions and an oxidizing agent in the oxidizing agent tank 2 is dropwisely introduced into the reactor 1, the oxidation reaction initiates and proceeds to produce an oxidized compound.
- the reactor 1 is provided with the ORP meter 5, and this ORP meter 5 detects the oxidation reduction potential of the reaction solution in the reactor 1 from the start of the oxidation reaction, and the detected values are inputted into the computer 6.
- the computer 6 functions as a determination means which at all time monitors the inputted detected value of the oxidation reduction potential and determines the end point of the oxidation reaction on the basis of the inflection point (highest electric potential) with the time course.
- the computer 6 performs the calculation for detecting the highest electric potential of the oxidation reduction potential and the calculation for detecting the amount of an electric potential dropped from the highest electric potential, and compares the dropped amount of the electric potential with the threshold value preliminarily set, so as to determine the end point of the oxidation reaction.
- the threshold value means the difference (amount of electric potential dropped) between the highest electric potential reached of the reaction solution and the electric potential at the end point of the oxidation reaction in the oxidation reaction carried out by the reactor, which is obtained by practically measuring the history of the oxidation reduction potential of the oxidation reaction solution in advance and then relating the history to the end point of the oxidation reaction confirmed from a quenching amount of the starting compound with TLC or the like.
- the dropped electric potential amount after reaching the highest electric potential which gives the end point of the oxidation reaction is 70 mV.
- the computer 6 has a CPU 6a for carrying out the determination process and a memory 6b for storing the program.
- the monitor 8 is a displaying means for displaying the history of the oxidation reduction potential monitored by the computer 6, and the operator can observe the change of the oxidation reduction potential of the oxidation reaction solution over a time course and the reaction end point with the monitor 8.
- the chart in Fig. 1 is an exemplary output chart of the oxidation reduction potential displayed on the monitor 8. The operator can swiftly stop the oxidation reaction by giving the order to the automatic valve 7 to supply an oxidation reaction terminating agent stored in the oxidation reaction terminating agent tank 4 to the reactor 1 after confirming the end point of the oxidation reaction with the monitor 8.
- an informing means such as a lamp or a buzzer which lights or alarms at the same time as the end point of the oxidation reaction is determined, thereby allowing the operator to more precisely recognize the end point of the oxidation reaction.
- the computer 6 is allowed to output a command signal x to the automatic valve 7 so as to supply an oxidation reaction terminating agent in the oxidation reaction terminating agent tank 4 to the reactor 1 when the end point of the oxidation reaction is determined, the oxidation reaction can be more promptly stopped, moving on to the next step is more swiftly done, and the production efficiency can be improved.
- a process for isolating insolubles by filtering the liquid in which precipitated crystals of the oxidized compound are dissolved, or the like can be carried out.
- concentration process by a solvent extraction of the oxidation reaction solution or the like, or the like may also be carried out, if necessary.
- the invention is particularly suitable for the oxidation reactions for obtaining the compound (II') from the compound (I') using an oxidizing agent, and among these particularly suitable for the oxidation reaction producing lansoprazole by oxidizing SUL with hydrogen peroxide.
- the invention also relates to a method of producing a remarkably stable crystal of an imidazole compound represented by the above general formula (II') or a salt thereof.
- the compound (II') is preferably a racemate, and it may be difficult to be directly applied to the optically active substance such as R-form and S-form of lansoprazole which has a different physicochemical characteristic to the racemate.
- the production method is characterized in that the remarkably stable crystal is produced from a solvate of the imidazole compound represented by the general formula (II') or a salt thereof by suspending the solvate into a solution having a pH of about 7 to 11 or into a solution containing water, an organic solvent (e.g., alcohol), and a basic substance.
- a solvate of the imidazole compound represented by the general formula (II') or a salt thereof by suspending the solvate into a solution having a pH of about 7 to 11 or into a solution containing water, an organic solvent (e.g., alcohol), and a basic substance.
- the solvate of the imidazole compound represented above by the general formula (II') or a salt thereof is not particularly limited in its production method and can be produced according to a method known per se, but preferably produced with remarkably high production efficiency by oxidizing an imidazole compound represented above by the general formula (I') or a salt thereof according to the above-mentioned method of producing the oxidized compound of the present invention, and then crystallizing from an organic solvent or an aqueous organic solvent.
- ketones e.g., acetone, methylethylketone, etc., esters e.g., ethyl acetate, etc., sulfoxides e.g., dimethylsulfoxide, etc., and amides e.g., dimethylformamide, etc.
- a crystal of solvate containing such solvent is obtained, and when a mixed solvent of alcohols e.g., methanol, ethanol, n-butanol, isobutanol, etc., ketones e.g., acetone, methylethylketone, etc., esters e.g., ethyl acetate, etc., sulfoxides e.g., dimethylsulfoxide, etc., amides e.
- alcohols e.g., methanol, ethanol, propanol, etc.
- ethanol is particularly preferable.
- the basic substance included in the above solution include amine such as ammonia and triethylamine, alkali metal hydroxide such as sodium hydroxide, calcium hydroxide, sodium carbonate, and sodium hydrogen carbonate, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, and the like, and ammonia is preferably used among them.
- the pH of the above solution is in the range of about 7 to 11, and preferably in the range of about 8 to 9, by adding the basic substance.
- the content of the organic solvent (preferably, alcohol) and the basic substance with respect to water in the above solution is not particularly limited, as long as it is the amount such that pH of the solution is ranging from about 7 to 11.
- the ratio of a water-organic solvent (preferably, alcohol) is from 10 to 500:1 (weight ratio), preferably from 20 to 200:1 (weight ratio), and more preferably from 20 to 100:1 (weight ratio).
- the ratio of a water-basic substance-organic solvent (preferably, alcohol) is from 10 to 500:0.0001 to 0.5:1 (weight ratio), preferably from 20 to 200:0.001 to 0.5:1 (weight ratio), and more preferably from 20 to 100:1 (weight ratio).
- the ratio of a water-ammonia water (25%)-organic solvent is from 10 to 500:0.005 to 0.5:1 (weight ratio), preferably from 20 to 200:0.005 to 0.1:1 (weight ratio), and more preferably from 20 to 100:0.005 to 0.1:1 (weight ratio).
- the content of alcohol with respect to water is very small in quantity (e.g., alcohol included as a crystalline solvent in the solvate or alcohol adhered on the surface of a crystal of the solvate (by the process of washing the crystal, or the like)), there is still an action and effect of improving the stability of the crystal to be obtained (crystal substantially not containing a solvent).
- the improvement in stability tends to become over the limit, and more likely to lower the quality of the crystal to be obtained.
- the alcohol content in the solution for suspending a crystal can be appropriately adjusted within the above range as described below, thus the action and effect of further improving the stability can be exhibited.
- the temperature of the above solution and the stirring period during suspending a solvate to the solution can be appropriately selected, but specifically, for example, the temperature of the solution is preferably from 20 to 40°C and more preferably from 24 to 30°C, and the stirring period is preferably from 10 to 120 minutes and more preferably from 30 to 60 minutes.
- the imidazole compound represented by the general formula (II') or a salt thereof is preferably lansoprazole or a salt thereof.
- a crystal form transformation of a solvate occurs, and the solvent is removed during this transformation.
- the decomposition of a crystal during the crystal form transformation can be prevented by including a basic substance into a solution in which the solvate is suspended, and the stability of the crystal to be obtained can be improved by appropriately adjusting the alcohol content within the above range.
- the SUL (compound of which R 2 is OCH 2 CF 3 , R 1 is CH 3 , R 3 is H, R 0 is H, and C' is a non-substituted benzene ring in the general formula (I')) which is a starting compound of lansoprazole can be obtained preferably by a series of reactions as shown in the following formula, and particularly, that the yield is improved when the condensation reaction at the second stage is carried out by adjusting the pH to 11.0 - 11.5, thereby being industrially advantageous.
- the invention can be suitably applied for a large-scale production of the compound useful as particularly a drug, and the like.
- a proton pump inhibitor typified by lansoprazole, an optically active substance thereof, or the like
- this product can be employed as an antiulcer agent, an anti H. pylori agent, or the like, for example, in accordance with the method disclosed in Japanese Unexamined Patent Publication No. S61-50978 or Japanese Unexamined Patent Publication No. H03-173817 .
- lansoprazole (1) The stability of the crystals of the solvate of lansoprazole obtained by vacuum drying the wet crystals of the solvate of ethanol-water of lansoprazole obtained according to the method in EXAMPLE 2, was compared to the stability of the white crystals of lansoprazole (hereinafter, referred to as lansoprazole (2)) obtained according to the method in EXAMPLE 3.
- the results for each of 3 samples for the lansoprazoles (1) and (2) are shown in the Table 1 below.
- the lansoprazole (2) is the crystal having more excellent stability as compared to the lansoprazole (1).
- an end point of an oxidation reaction can be simply determined by the method of producing an oxidized compound of the invention, thus moving on to the next step after terminating the oxidation reaction is more swiftly achieved.
- the production efficiency of the oxidized compound in an industrial production process can be greatly improved.
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JP2004265717 | 2004-09-13 | ||
EP05785895.3A EP1790647B1 (fr) | 2004-09-13 | 2005-09-13 | Procede destines a produire un compose oxyde |
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US (2) | US8592598B2 (fr) |
EP (2) | EP2264025B1 (fr) |
JP (2) | JP5173191B2 (fr) |
KR (2) | KR101276915B1 (fr) |
CN (2) | CN102775388B (fr) |
CA (2) | CA2787378C (fr) |
ES (2) | ES2441970T3 (fr) |
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WO2009066309A2 (fr) * | 2007-07-12 | 2009-05-28 | Cadila Healthcare Limited | Procédé de préparation d'oméprazole |
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2005
- 2005-09-13 JP JP2006535242A patent/JP5173191B2/ja active Active
- 2005-09-13 EP EP10177460.2A patent/EP2264025B1/fr active Active
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- 2005-09-13 KR KR1020077008174A patent/KR101276915B1/ko active IP Right Grant
- 2005-09-13 CA CA2787378A patent/CA2787378C/fr active Active
- 2005-09-13 ES ES05785895T patent/ES2406959T3/es active Active
- 2005-09-13 WO PCT/JP2005/017222 patent/WO2006030936A1/fr active Application Filing
- 2005-09-13 CA CA2579665A patent/CA2579665C/fr active Active
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- 2005-09-13 KR KR1020127017117A patent/KR101376360B1/ko active IP Right Grant
- 2005-09-13 CN CN2005800386275A patent/CN101056869B/zh active Active
- 2005-09-13 US US11/662,740 patent/US8592598B2/en active Active
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- 2013-10-31 US US14/068,749 patent/US9346783B2/en active Active
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EP1790647A1 (fr) | 2007-05-30 |
ES2406959T3 (es) | 2013-06-10 |
KR101276915B1 (ko) | 2013-06-19 |
CN101056869B (zh) | 2012-09-26 |
US20080262235A1 (en) | 2008-10-23 |
EP2264025B1 (fr) | 2013-11-06 |
US9346783B2 (en) | 2016-05-24 |
JP2012121897A (ja) | 2012-06-28 |
JP5677333B2 (ja) | 2015-02-25 |
IL181751A (en) | 2013-04-30 |
JP5173191B2 (ja) | 2013-03-27 |
CA2787378C (fr) | 2015-11-03 |
KR101376360B1 (ko) | 2014-03-20 |
WO2006030936A1 (fr) | 2006-03-23 |
US20140100370A1 (en) | 2014-04-10 |
CN101056869A (zh) | 2007-10-17 |
CA2579665C (fr) | 2014-03-18 |
CN102775388A (zh) | 2012-11-14 |
JPWO2006030936A1 (ja) | 2008-05-15 |
IL214791A0 (en) | 2011-09-27 |
CN102775388B (zh) | 2016-01-20 |
US8592598B2 (en) | 2013-11-26 |
EP1790647B1 (fr) | 2013-05-08 |
KR20130026417A (ko) | 2013-03-13 |
CA2787378A1 (fr) | 2006-03-23 |
KR20070057926A (ko) | 2007-06-07 |
ES2441970T3 (es) | 2014-02-07 |
IL181751A0 (en) | 2007-07-04 |
EP1790647A4 (fr) | 2009-08-05 |
CA2579665A1 (fr) | 2006-03-23 |
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